Substituted 3-hydroxy-delta-lactones from epoxides

ABSTRACT

Catalysts and methods for the carbonylation of epoxides to substituted 3-hydroxy-δ-lactones and β-lactones are disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. provisional application Ser.No. 61/116,609, filed Nov. 20, 2008, the entirety of which is herebyincorporated herein by reference.

GOVERNMENT SUPPORT

This work was supported by the National Science Foundation (CHE-0243605)and the Department of Energy (DE-FG02-05ER15687) and by the NationalInstitutes of Health through a Chemical/Biology Interface (CBI) TrainingGrant.

BACKGROUND

Substituted 3-hydroxy-δ-lactones (3HLs) are common structural motifs innatural products (Aggarwal et al., Tetrahedron 2004, 60, 9726-9733) andare valuable as intermediates in the synthesis of a variety ofpharmaceutical compounds (Aggarwal et al., Tetrahedron 2004, 60,9726-9733; Sharma et al., J. Org. Chem. 1999, 64, 8059-8062; Cefalo etal., J. Am. Chem. Soc. 2001, 123, 3139-3140; Stevenson, R.; Weber, J. V.J. Nat. Prod. 1988, 51, 1215-1219). 3HLs are most prominent in the classof HMG-CoA reductase inhibitors known as statins, which are among themost potent cholesterol-lowering drugs available and constitute five ofthe top 100 selling drugs (Tolbert et al., Nat. Rev. Drug. Discovery,2003, 2, 517-526; de Lorenzo et al., Curr. Med. Chem. 2006, 13,3385-3393). All approved statins have side chains comprised of either a3HL or the hydrolyzed 3,5-dihydroxycarboxylic acid analog (FIG. 1),which are essential for the bioactivity of statin drugs (Aggarwal etal., Tetrahedron 2004, 60, 9726-9733). 3HLs have also been used in thesynthesis of important drugs such as tetrahydrolipstatin (Sharma et al.,J. Org. Chem. 1999, 64, 8059-8062), a lipase inhibitor prescribed forthe treatment of obesity, and the antiretroviral agent tipranavir(Cefalo et al., J. Am. Chem. Soc. 2001, 123, 3139-3140). Furthermore,dehydration of 3HLs produces a class of biologically activeα,β-unsaturated lactone natural products (Stevenson, R.; Weber, J. V. J.Nat. Prod. 1988, 51, 1215-1219).

As a result of their synthetic value, the synthesis of 3HLs has receiveda great deal of attention in recent years (Gijsen et al., J. Am. Chem.Soc. 1995, 117, 7585-7591; Heine et al., J. Mol. Biol. 2004, 343,1019-1034; Loubinoux et al., Tetrahedron 1995, 51, 3549-3558; Kim etal., Synthesis 2001, 1790-1793; Le Sann et al., Org. Biomol. Chem. 2005,3, 1719-1728; Reddy et al., J. Organomet. Chem. 2001, 624, 239-243;Fournier et al., Synlett 2003, 107-111). Biocatalytic routes have provensuccessful in the synthesis of statin side chains, though substratescope is limited (Gijsen et al., J. Am. Chem. Soc. 1995, 117, 7585-7591;Heine et al., J. Mol. Biol. 2004, 343, 1019-1034). Synthetic routes tosubstituted 3HLs have employed a variety of methods, including aldolreactions using chiral auxiliaries, reduction of diketoesters followedby cyclization, allyl boration and ring-closing metathesis, andrearrangement of (3-lactones (Fournier et al., Synlett 2003, 107-111).These methods, however, involve multiple steps and can suffer from lowstereoselectivity. Thus, there remains a need for improved methodologiesto synthesize substituted 3-hydroxy-δ-lactones (3HLs). The presentinvention provides such a methodology.

SUMMARY

In one aspect the present disclosure provides methods for synthesizingsubstituted 3-hydroxy-δ-lactones by carbonylation of epoxides. Inparticular, it has been unexpectedly found that, under certainconditions, the carbonylation of epoxides proceeds to affordpredominantly δ-lactones, rather than the expected β-lactone.

In general these methods comprise the steps of:

reacting an epoxide of formula:

wherein R_(a), R_(b), R_(c), R_(d), R, P′, and n are as defined below;

with carbon monoxide (CO) in the presence of a catalytically effectiveamount of a catalyst of the formula:[Lewis acid]^(u+){[QT(CO)_(v)]^(s−)}^(t)  II

wherein Q, T, s, t, u, and v are as defined below;

to produce a compound of the formula:

In another aspect the present disclosure provides methods forsynthesizing β-lactones by carbonylation of epoxides.

All publications and patent documents cited in this application areincorporated by reference in their entirety for all purposes to the sameextent as if the contents of each individual publication or patentdocument were incorporated herein.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1. Structures of two common statin drugs with 3HL portionhighlighted.

FIG. 2. Carbonylation of 4-hydroxy-1,2-epoxynonane (6) monitored by insitu IR spectroscopy.

FIG. 3. β-Lactone 8 and δ-lactone 7 under standard reaction conditionsmonitored by in situ IR spectroscopy. The spike and subsequent drop inabsorbances at 40 minutes is due to venting the CO pressure in thereactor and dilution of the reaction mixture by addition of catalystsolution. The unchanging absorbances of both lactones after catalystaddition indicates that 7 is not formed from 8, and therefore 8 is notan intermediate in the carbonylation reaction.

FIG. 4. Proposed Mechanism for Competing δ-Lactone and β-Lactoneformation.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

The present disclosure provides catalysts and methods that enable thecarbonylation of epoxides to provide δ-lactone products and, undercertain conditions, β-lactone products. In general, the carbonylation isperformed on substituted homoglycidols and proceeds with retention ofstereochemistry where stereocenters exist. While methods that producehigh crude yields of δ-lactone are most useful (e.g., at least 50%, atleast 70%, at least 80%, at least 90%, at least 95%, etc.), the presentinvention also encompasses methods that generate lower crude yields(e.g., at least 10%, at least 20%, etc.) of δ-lactone, or some amount ofβ-lactone product. The present disclosure also describes methods thatenable the carbonylation of epoxides to provide certain β-lactoneproducts.

In various embodiments, the present disclosure provides a method ofproducing a δ-lactone, comprising the steps of:

reacting an epoxide of formula:

wherein R_(a), R_(b), R_(c), R_(d), P′, R and n are as defined below;

with carbon monoxide (CO) in the presence of a catalytically effectiveamount of a catalyst of the formula:[Lewis acid]^(u+){[QT(CO)_(v)]^(s−}) ^(t)  II

wherein Q, T, s, t, u, and v are as defined below;

to produce a compound of the formula:

Epoxides

The methods are generally applicable and a wide range of epoxidestarting materials can be used. The epoxide substrates may bemonosubstituted, vicinally disubstituted (either cis or trans),geminally disubstituted, trisubstituted or tetrasubstituted epoxidesthough these highly substituted substrates react more slowly and tend togive lower yields of product. The substituent(s) on the epoxide can beany that are compatible with the reaction conditions described herein.

In certain embodiments, the epoxide has the formula I:

wherein n is an integer between 0 and 3, inclusive; and the R_(a),R_(b), R_(e), R_(d), P′ and R groups, and any other chemical variableappearing in the Schemes and structures described herein, encompassthose chemical moieties and functional groups that would be recognizedby one having skill in the art of organic chemistry as being compatiblewith the structure and function of the molecules bearing those chemicalvariables. Exemplary functional groups include substituted andunsubstituted, cyclic and acyclic hydrocarbon moieties, substituted andunsubstituted, cyclic and acyclic heteroatom-containing moieties, aswell as common functional groups comprising heteroatoms, halogens, andmetalloid elements.

To further define the range of suitable groups certain definitions areprovided below. Nonetheless, it is to be understood that thesedefinitions are meant to be representative and the absence of a specificgroup or moiety in the definitions below is not necessarily meant toexclude such groups or to imply that such a group is not encompassed bythe present invention.

In any case where a chemical variable is shown attached to a bond thatcrosses a bond of ring (for example as shown for R above) this meansthat one or more such variables are optionally attached to the ringhaving the crossed bond. Each R group on such a ring can be attached atany suitable position, this is generally understood to mean that thegroup is attached in place of a hydrogen atom on the parent ring. Thisincludes the possibility that two R groups can be attached to the samering atom. Furthermore, when more than one R group is present on a ring,each may be the same or different than other R groups attached thereto,and each group is defined independently of other groups that may beattached elsewhere on the same molecule, even though they may berepresented by the same identifier. Furthermore, when two or more Rgroups are present, they may be taken together with intervening atoms toform cyclic structures. Such cyclics may optionally contain heteroatomsor sites of unsaturation and may be further substituted with one or moreX groups.

In one embodiment of the epoxides of formula I, R_(a), R_(b) R_(c),R_(d), and each R group can be independently selected from the groupconsisting of: hydrogen; halogen; (a) C₁ to C₂₀ alkyl; (b) C₂ to C₂₀alkenyl; (c) C₂ to C₂₀ alkynyl; (d) up to a C₁₂ carbocycle; (e) up to aC₁₂ heterocycle; (f) —C(R¹³)_(z)H_((3-z)); and (g) a polymer chain. Twoor more of R_(a), R_(b), R_(c), R_(d), or R groups may be taken togetherwith the carbon atoms to which they are attached to form one or morerings, and any of (a) through (e) may optionally be further substitutedwith one or more X groups.

In one embodiment of the epoxides of formula I, P′ is hydrogen or asuitable protecting group capable of being cleaved in situ. Suitableprotecting groups may be any of those known in the art. In certainembodiments, P′ is a protecting group selected from those described indetail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G.M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999, the entirety of whichis incorporated herein by reference.

X at each occurrence can be independently selected from the groupconsisting of: halogen; —OR¹⁰; —OC(O)R¹³; —OC(O)OR¹³; —OC(O)NR¹¹R¹²;—CN; —CNO; —C(O)R¹³; —C(O)OR¹³; —C(O)NR¹¹R¹²; —C(R¹³)_(z)H_((3-z));—NR¹¹C(O)R¹⁰; —NR¹¹C(O)OR¹⁰; —NCO; —NR¹²SO₂R¹³; —[P(R¹³)₃]⁺;—P═O(OR¹⁰)₂; —S(O)_(x)R¹³; —S(O)₂NR¹¹R¹²; —NO₂; —N₃; —(CH₂)_(k)R¹⁴;—(CH₂)_(k)—Z—R¹⁴; and —(CH₂)_(k)—Z—(CH₂)_(m)—R¹⁴.

R¹⁰ at each occurrence can be independently selected from the groupconsisting of: hydrogen; —C(R¹³)_(z)H_((3-z)); C₁ to C₁₂ alkyl; C₂ toC₁₂ alkenyl; C₂ to C₁₂ alkynyl; up to a C₁₂ carbocycle; up to a C₁₂heterocycle; S(O)₂R¹³; —Si(R¹⁵)₃; and a hydroxyl protecting group.

R¹¹ and R¹² at each occurrence can be independently selected from thegroup consisting of: hydrogen; C₁ to C₁₂ alkyl; C₂ to C₁₂ alkenyl; C₂ toC₁₂ alkynyl; and —C(R¹³)_(z)H_((3-z)). R¹¹ and R¹²; when both present,can optionally be taken together with the atom to which they areattached to form a 3- to 10-membered ring.

R¹³ at each occurrence can be independently selected from the groupconsisting of: hydrogen; halogen; C₁ to C₁₂ alkyl; C₂ to C₁₂ alkenyl; C₂to C₁₂ alkynyl; up to a C₁₂ carbocycle; and up to a C₁₂ heterocycle.

R¹⁴ at each occurrence can be independently selected from the groupconsisting of: halogen; —OR¹⁰; —OC(O)R¹³; —OC(O)OR¹³; —OC(O)NR¹¹R¹²;—CN; —CNO; —C(R¹³)_(z)H_((3-z)); —C(O)R¹³; —C(O)OR¹³; —C(O)NR¹¹R¹²;—NR¹¹C(O)R¹³; —NR¹¹C(O)OR¹⁰; —NR¹¹SO₂R¹³; —NCO; —N₃; —NO₂; —S(O)_(x)R¹³;—SO₂NR¹¹R¹²; up to a C₁₂ heterocycle; and up to a C₁₂ carbocycle.

R¹⁵ at each occurrence can be independently selected from the groupconsisting of: C₁ to C₆ alkyl; C₂ to C₆ alkenyl; C₂ to C₆ alkynyl; andup to C₁₂ substituted or unsubstituted carbocycle.

Z is a divalent linker and can be selected from the group consisting of:—(CH═CH)_(a)—; —(CH≡CH)_(a)—; —C(O)—; —C(═NOR¹¹)—; —C(═NNR¹¹R¹²)—; —O—;—N(R¹¹)—; —N(C(O)R¹³)—; —S(O)_(x)—; a polyether; and a polyamine.

a can be 1, 2, 3, or 4.

k can be an integer from 1 to 8 inclusive.

m can be an integer from 1 to 8 inclusive.

x can be 0, 1, or 2.

z can be 1, 2, or 3.

In certain embodiments, R is an optionally substituted branchedaliphatic moiety.

In certain embodiments, the epoxide is of the formula

wherein p is an integer between 0 and 10, inclusive. In certainembodiments, R_(c), R_(d), and R are hydrogen. In some embodiments, p is0. In some embodiments, p is 1. In some embodiments, p is 2. In someembodiments, p is 3. In some embodiments, p is 4.

In certain embodiments, the epoxide is of the formula

In certain embodiments, the epoxide is of the formula

In certain embodiments, the epoxide is of the formula

In certain embodiments, the epoxide is of the formula

wherein m is an integer between 0 and 10, inclusive. In certainembodiments, m is 2. In certain embodiments, m is 9. In certainembodiments, m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In certainembodiments, n is 0. In some embodiments, P′ is hydrogen.

In some of these embodiments, the epoxide is of the formula

In certain embodiments, the epoxide is of the formula

In certain embodiments, X is halogen. In certain embodiments, X ischlorine.

In certain embodiments, X is a phosphorous containing functional group.In certain embodiments, X is a phosphonium salt. In certain embodiments,X is —[P(R¹³)₃]⁺. In certain embodiments, X is triarylphosphonium. Incertain embodiments, X is triphenylphosphonium. In certain embodiments,X is a phosphonate group. In certain embodiments, X is P═O(OR¹⁰)₂. Incertain embodiments, X is P═O(OMe)₂. In certain embodiments, X isP═O(OEt)₂.

In certain embodiments, X is a keto group ═O. In certain embodiments, Xis an acetal group.

In certain embodiments the epoxide is of the formula

In certain embodiments, the epoxide is of the formula

In some embodiments, R¹⁰ and P′ are hydrogen. In some embodiments, R¹⁰and P′ are suitable protecting groups. In certain embodiments, asuitable protecting group is a silyl protecting group. In someinstances, the suitable protecting group is tert-butyldimethylsilyl.

In certain embodiments, the epoxide is of the formula

In some embodiments, R¹⁰ is an aliphatic group optionally substitutedwith fluorine.

In certain embodiments, the epoxide is of the formula

In certain embodiments, the epoxide is of the formula

In certain embodiments, the epoxide is of the formula

In certain embodiments, the epoxide is of the formula

In some embodiments, n is 0. In some embodiments, P′ is hydrogen.

In certain embodiments, the epoxide is of the formula

Where different stereoisomers of an epoxide can exist, the epoxide mayor may not contain more than one stereoisomer. In certain embodiments,the epoxide may be a single enantiomer or diastereomer. In certainembodiments, the epoxide is of the formula

In certain embodiments wherein the epoxide is enantiopure, carbonylationmay proceed with retention of stereochemistry.

It is to be understood that the present invention encompasses the use ofepoxides which comprise any combination of these variable definitions.

These representative epoxides demonstrate that the methods areapplicable to a range of substituted epoxide substrates including thosecontaining alcohols, ethers, silyl ethers, alkenes and halogens. It isto be understood that these lists are not exhaustive and that otherfunctional groups can also be present.

In certain embodiments, the 3-hydroxy-δ-lactones produced according tothe disclosed methods are useful as pharmaceutical compounds or asintermediates in the synthesis of pharmaceutical compounds. In certainembodiments, the disclosed methods are useful in the synthesis ofcholesterol-lowering agents. In certain embodiments, the presentinvention provides methods for the synthesis of statin drugs and theirderivatives and precursors.

In certain embodiments, the 3-hydroxy-δ-lactones produced by methods ofthe invention represent a statin sidechain having the formula S-I:

where Q′ is as defined herein.

In certain embodiments, the invention encompasses methods comprising thestep of carbonylating an epoxide of formula S-Ia with a carbonylationcatalyst and CO to provide a compound of formula S-I:

In certain embodiments, the methods further include the step of openingthe lactone ring to provide molecules, of structure S-II:

In certain embodiments, the ring opening step is performed in thepresence of water and R in structure S-II is H.

In certain embodiments, the starting epoxide is enantioenriched and themethod provides statin-like compounds with defined stereochemistry suchas S-I′:

In certain embodiments -Q′ in the above schemes and structures isselected from the group consisting of: hydrogen; halogen; (a) C₁ to C₂₀alkyl; (b) C₂ to C₂₀ alkenyl; (c) C₂ to C₂₀ alkynyl; (d) up to a C₁₆carbocycle; (e) up to a C₁₋₆ heterocycle; (f) —C(R¹³)_(z)H_((3-z)); and(g) a polymer chain.

In certain embodiments Q′ in the above schemes and structures isselected from the group consisting of the core of a statin compound or aprecursor or derivative of such a compound. In certain embodiments, Q′is the core of a compound selected from the group consisting of:atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin,pitavastatin, pravastatin, rosuvastatin, and simvastatin.

In certain embodiments, the invention comprises methods to produceatorvastatin, and precursors and derivatives thereof. In certainembodiments, the moiety

is selected from the group consisting of:

where R¹¹, R¹², and R¹³ are as defined herein above and R^(e) is asdefined below.

In certain embodiments, the invention comprises methods to producecerivastatin and precursors and derivatives thereof. In certainembodiments, the moiety

is selected from the group consisting of:

where R¹⁰ and R¹³ are as defined herein above and R^(e) is as definedbelow.

In certain embodiments, the invention comprises methods to producefluvastatin, and precursors and derivatives thereof. In certainembodiments, the moiety

is selected from the group consisting of:

In certain embodiments, the invention comprises methods to producelovastatin, and precursors and derivatives thereof. In certainembodiments, the moiety

is selected from the group consisting of:

where R¹⁰ and R¹³ are as defined herein above and R^(e) and R^(f) are asdefined below.

In certain embodiments, the invention comprises methods to producesimvastatin, and precursors and derivatives thereof. In certainembodiments, the moiety

is selected from the group consisting of:

where R¹³ is as defined herein above and R^(e) is as defined below.

In certain embodiments, the invention comprises methods to producemevastatin, and precursors and derivatives thereof. In certainembodiments, the moiety

is selected from the group consisting of:

where R¹⁰ and R¹³ are as defined herein above.

In certain embodiments, the invention comprises methods to producepravastatin, and precursors and derivatives thereof. In certainembodiments, the moiety

is selected from the group consisting of:

where R¹⁰ and R¹³ are as defined hereinabove and R^(e) is as definedbelow.

In certain embodiments, the invention comprises methods to producepitavastatin, and precursors and derivatives thereof. In certainembodiments, the moiety

is selected from the group consisting of:

where R¹³ is as defined herein above and R^(e) is as defined below.

In certain embodiments, the invention comprises methods to producerosuvastatin, and precursors and derivatives thereof. In certainembodiments, the moiety

is selected from the group consisting of:

where R¹⁰ R¹¹ R¹² and R¹³ are as defined herein above and R^(e) is asdefined below.Catalysts

As described generally above, the present invention encompasses the useof carbonylation catalysts of formula II:[Lewis acid]^(u+){[QT(CO)_(v)]^(s−)}^(t)  II

wherein:

Q is any ligand or set of ligands and need not be present;

T is a transition metal;

s is an integer from 1 to 4 inclusive;

t is a number such that t multiplied by s equals u;

u is an integer from 1 to 6 inclusive; and

v is an integer from 1 to 9 inclusive.

In some embodiments, v is an integer from 1 to 4 inclusive. In certainembodiments, v is 4.

In certain embodiments, u and s are both 1. In certain embodiments, uand s are both 2.

Transition Metal Carbonyl Complexes

The transition metal carbonyl complex included in the catalyst may beneutral or anionic. In certain embodiments, the metal carbonyl complexis anionic, e.g., monoanionic carbonyl complexes of metals from groups5, 7 or 9 of the periodic table or dianionic carbonyl complexes ofmetals from groups 4 or 8 of the periodic table. In certain embodiments,the metal carbonyl complex contains a metal from group 9 of the periodictable, e.g., cobalt. In certain embodiments [Co(CO)₄]⁻ may be used.

In some embodiments, the transition metal carbonyl complex of acarbonylation catalyst is neutral and no Lewis acid as set forth informula II is present. In certain embodiments, the carbonylationcatalyst is Co₂(CO)₈.

While the metal carbonyl complexes disclosed herein are generally binarymetal carbonyl complexes (i.e., they have the formula T(CO)_(v) andconsist only of a metal and carbonyl ligands) this is not a limitingrequirement of the present invention, and the use of mixed ligand metalcarbonyl complexes is also contemplated. For example, a bidentatephosphine ligand may be present along with the carbonyl ligands. It isalso anticipated that under some reaction conditions, mixed ligandcarbonyl complexes may be formed in situ from the binary complexesduring the reaction. Whether added or formed in situ, catalystscontaining mixed ligand carbonyl complexes are encompassed by thepresent invention.

In some cases, the metal atom of the Lewis acid can be coordinated toone or more additional neutral coordinating ligands (for instance tosatisfy the metal atom's coordination valence) one such ligand that isparticularly preferred is tetrahydrofuran (THF), it will be understoodhowever that many other solvents and other ligands such as are wellknown in the art may also fulfill this role without departing from thepresent invention. It will also be realized that under reactionconditions, the coordinating ligands can be replaced by reagents,products, intermediates or solvents that may be present. Such insitu-generated species are also encompassed by the present invention. Aswith many catalytic processes, the structure of the specific catalystadded to the reaction will not always be the active species.

Lewis Acids

In some embodiments, the present invention encompasses the use ofcarbonylation catalysts comprising a complex of formula [Lewisacid]^(u+){[QT(CO)_(v)]^(s−)}^(t), wherein Q, T, s, t, u, and v are asdefined above. In some embodiments, the Lewis acid is H⁺. In certainembodiments, a carbonylation catalyst is of the formula HCo(CO)₄. Insome embodiments, Lewis acids are metal complexes of the formula[M(L)_(b)]^(c+) (e.g., where M is a metal, each L is a ligand and neednot be present, b is an integer from 1 to 6 inclusive, and c is 1, 2, or3, and where, if more than one L is present, each L may be the same ordifferent). In certain embodiments, M is a transition metal or a group13 or 14 metal. For example, in some embodiments, M is aluminum,chromium, or titanium. In certain embodiments, M is aluminum.

Similarly, a range of ligands (L) can be present in the Lewis acid ofthe carbonylation catalyst. In certain embodiments a ligand can be adianionic tetradentate ligand. In some embodiments, a ligand can be asolvent such as THF. In certain embodiments, Lewis acids of thecarbonylation catalyst contain a combination of one or more dianionictetradentate ligands and one or more solvent ligands (e.g., THF).

Suitable ligands include, but are not limited to, porphyrin derivativesof formula IIIa, salen derivatives of formula IIIb, and metallocenederivatives of formula IIIc, below. In some cases, a mixture of morethan one Lewis acid can be present in the catalyst. Exemplarydefinitions for the R groups appearing in structures IIIa, IIIb, andIIIc are more fully described above and herein.

In certain embodiments, a Lewis acid of a carbonylation catalyst is offormula IIIa:

wherein:

-   M is a metal;-   L is a ligand and need not be present;-   R^(e) at each occurrence is independently selected from the group    consisting of: hydrogen; C₁-C₁₂ alkyl; C₂-C₁₂ alkenyl; C₂-C₁₂    alkynyl; aryl; heteroaryl; halogen; —OR¹⁰; —OC(O)R¹³; —OC(O)OR¹³;    —OC(O)NR¹¹R¹²; —CN; —CNO; —C(O)R¹³; —C(R¹³)_(z)H_((3-z)); —C(O)OR¹³;    —C(O)NR¹¹R¹²; —NR¹¹R¹²; —NR¹¹C(O)R¹⁰; —NR¹¹C(O)OR¹³; —NR¹¹SO₂R¹³;    —NCO; —N₃; —NO₂; —S(O)_(x)R¹³; —SO₂NR¹¹R¹²; —C(R¹³)_(z)H_((3-z));    —(CH₁₂)_(k)R¹⁴; —(CH₂)_(k)—Z—R¹⁶—; and —(CH₂)_(k)—Z—(CH₂)_(m)—R¹⁴;    where two or more Re groups can optionally be taken together with    intervening atoms to form an optionally substituted carbocyclic or    heterocyclic ring, and-   R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁶, Z, k, m, x, and z are as defined    above.

In some embodiments, each occurrence of R^(e) is independently hydrogen;halogen; C₁-C₁₂ alkyl; C₂-C₁₂ alkenyl; C₂-C₁₂ alkynyl; aryl; orheteroaryl.

In some embodiments, each occurrence of R^(e) is independently hydrogen,halogen, or C₁-C₆ alkyl. In certain embodiments, each occurrence ofR^(e) is independently methyl, ethyl, propyl, or butyl. In certainembodiments, R^(e) is ethyl.

In some embodiments, each occurrence of R^(e) is independently aryl. Incertain embodiments, each occurrence of R^(e) is independently phenyloptionally substituted with 1-3 substituents selected from the groupconsisting of fluorine, chlorine, methyl, trifluoromethyl, methoxy,and/or trifluoromethoxy. In certain embodiments, each occurrence ofR^(e) is independently phenyl substituted at the para position with asubstituent selected from the group consisting of fluorine, chlorine,methyl, trifluoromethyl, methoxy, or trifluoromethoxy. In certainembodiments, each occurrence of R^(e) is independently phenylsubstituted at the ortho and para positions with methyl.

In some embodiments, a Lewis acid of the carbonylation catalyst is offormula IIIa, wherein M is Al.

In some embodiments, a Lewis acid of the carbonylation catalyst is offormula IIIa, wherein L is a solvent. In certain embodiments, a Lewisacid of the carbonylation catalyst is of formula IIIa and L is anethereal solvent. In certain embodiments, a Lewis acid of thecarbonylation catalyst is of formula IIIa and each L is THF.

In some embodiments, a Lewis acid of the carbonylation catalyst is offormula IIIa(i):

wherein L, M, and R^(e) are as defined above and herein. In someembodiments, a Lewis acid of the carbonylation catalyst is of formulaIIIa(i), wherein M is Al or Cr. In some embodiments, a Lewis acid of thecarbonylation catalyst is of formula IIIa(i), wherein L is a solvent. Incertain embodiments, a Lewis acid of the carbonylation catalyst is offormula IIIa(i) and L is an ethereal solvent. In certain embodiments, aLewis acid of the carbonylation catalyst is of formula IIIa(i) and eachL is THF.

In some embodiments, a Lewis acid of the carbonylation catalyst is offormula IIIa(ii):

wherein L and M are as defined above and herein.

In some embodiments, a Lewis acid of the carbonylation catalyst is offormula IIIa(ii), wherein L is a solvent. In certain embodiments, aLewis acid of the carbonylation catalyst is of formula IIIa(ii) and L isan ethereal solvent. In certain embodiments, a Lewis acid of thecarbonylation catalyst is of formula IIIa(ii) and each L is THF. Incertain embodiments, wherein a Lewis acid of the carbonylation catalystis of formula IIIa(ii), the transition metal complex is [Co(CO)₄]⁻. Incertain embodiments, wherein a Lewis acid of the carbonylation catalystis of formula IIIa(ii), M is Al or Cr.

In certain embodiments, a carbonylation catalyst is of formula IIa(i):

In certain embodiments, a carbonylation catalyst is of formula IIa(ii):

In certain embodiments, a Lewis acid of the carbonylation catalyst is offormula IIIb:

wherein:

-   R¹ and R^(1′) are independently selected from the group consisting    of: hydrogen; C₁ to C₁₂ alkyl; C₂ to C₁₂ alkenyl; C₂ to C₁₂ alkynyl;    —C(R¹³)_(z)H_((3-z)); —(CH₂)_(k)R¹⁴; and —(CH₂)_(k)—Z—R¹⁴;-   R², R^(2′), R³, and R^(3′) are independently selected from the group    consisting of:    -   (i) C₁-C₁₂ alkyl; (ii) C₂-C₁₂ alkenyl; (iii) C₂-C₁₂        alkynyl; (iv) up to a C₁₂ carbocycle; (v) up to a C₁₂        heterocycle; (vi) —(CH₂)_(k)R¹⁴; (vii) R²⁰; and (viii)        —C(R¹³)_(z)H_((3-z)),        -   wherein each of (i) through (v) may optionally be further            substituted with one or more R²⁰ groups; and where R² and            R³, and R^(2′) and R^(3′) may optionally be taken together            with the carbon atoms to which they are attached to form one            or more rings which may in turn be substituted with one or            more R²⁰ groups;-   R⁴ is selected from the group consisting of:

-   -   wherein X is a divalent linker selected from the group        consisting of: —N(R¹¹)—; —S(O)_(x); —(CH₂)_(k)—; —C(O)—;        —C(═NOR¹⁰)—; —C(R^(f))₂—; a polyether; a C₃ to C₈ substituted or        unsubstituted carbocycle; and a C₁ to C₈ substituted or        unsubstituted heterocycle;        -   R^(e) is as defined above;        -   R^(f) at each occurrence is independently selected from the            group consisting of: (a) C₁-C₁₂ alkyl; (b) C₂-C₁₂            alkenyl, (c) C₂-C₁₂ alkynyl; (e) up to a C₁₂ carbocycle, (f)            up to a C₁₂ heterocycle; (g) R²⁰; and (h)            —C(R¹³)_(z)H_((3-z)); or wherein:            -   two or more R^(f) groups may be taken together with                intervening atoms to form one or more rings; or            -   wherein when two R^(f) groups are attached to the same                carbon atom, they may be taken together to form a moiety                selected from the group consisting of: a 3- to                8-membered spirocyclic ring; a carbonyl (C═O), an                oxime)(C═NOR¹⁰; a hydrazone (C═NNR¹¹R¹²); an imine                (C═NR¹¹); and an alkenyl group (C═CR¹¹R¹²);

-   R²⁰ at each occurrence is independently selected from the group    consisting of: hydrogen; halogen; —OR¹⁰; —OC(O)R¹³; —OC(O)OR¹³;    —OC(O)NR¹¹R¹²; —CN; —CNO; —C(O)R¹³; —C(O)OR¹³; —C(O)NR¹¹R¹²;    —C(R¹³)_(z)H_((3-z)); —NR¹¹R¹²; —NR¹¹C(O)R¹⁰; —NR¹¹C(O)OR¹⁰; —NCO;    —NR¹²SO₂R¹³; —S(O)_(x)R¹³; —S(O)₂NR¹¹R¹²; —NO₂; —N₃; —(CH₂)_(k)R¹⁴;    —(CH₂)_(k)—Z—R¹⁶; and —(CH₂)_(k)—Z—(CH₂)_(m)—R¹⁴; and

-   L, M, R¹⁰, R¹¹, R¹²; R¹³, R¹⁴, R¹⁶, Z, k, m, x, and z are as defined    above.

In some embodiments, R² and R³, and R^(2′) and R^(3′) may optionally betaken together with the carbon atoms to which they are attached to formone or more rings which may in turn be substituted with one or more R²⁰groups. In certain embodiments, R² and R³, and R^(2′) and R^(3′) mayoptionally be taken together with the carbon atoms to which they areattached to form phenyl substituted with one or more R²⁰ groups. Incertain embodiments, R² and R³, and R^(2′) and R^(3′) may optionally betaken together with the carbon atoms to which they are attached to formphenyl substituted with one or more C₁₋₁₂ alkyl groups.

In certain embodiments, R² and R³, and R^(2′) and R^(3′) are both offormula:

In some embodiments, R⁴ is of formula:

In some embodiments, a Lewis acid of the carbonylation catalyst is offormula IIIb, wherein M is Al or Cr. In some embodiments, a Lewis acidof the carbonylation catalyst is of formula IIIb, wherein L is asolvent. In certain embodiments, a Lewis acid of the carbonylationcatalyst is of formula IIIb and L is an ethereal solvent. In certainembodiments, a Lewis acid of the carbonylation catalyst is of formulaIIIb and each L is THF.

In some embodiments, a Lewis acid of the carbonylation catalyst is offormula IIIb(i):

wherein L, M, and R^(e) are as defined above and herein.

In some embodiments, a Lewis acid of the carbonylation catalyst is offormula IIIb(i), wherein L is a solvent. In certain embodiments, a Lewisacid of the carbonylation catalyst is of formula IIIb(i) and L is anethereal solvent. In certain embodiments, a Lewis acid of thecarbonylation catalyst is of formula IIIb(i) and each L is THF. Incertain embodiments, wherein a Lewis acid of the carbonylation catalystis of formula IIIb(i), the transition metal complex is [Co(CO)₄]⁻. Incertain embodiments, wherein a Lewis acid of the carbonylation catalystis of formula IIIb(i), each R^(e) is independently C₁-C₆ alkyl. Incertain embodiments, wherein a Lewis acid of the carbonylation catalystis of formula IIIb(i), each R^(e) is t-butyl. In some embodiments, aLewis acid of the carbonylation catalyst is of formula IIIb(i), whereinM is Al or Cr.

In certain embodiments, a carbonylation catalyst is of formula IIb(i):

In certain embodiments, a carbonylation catalyst is of formula IIb(ii):

In some embodiments, a Lewis acid of a carbonylation catalyst is offormula IIIc:

wherein L and M are as defined above and herein.

In some embodiments, a Lewis acid of the carbonylation catalyst is offormula IIIc, wherein L is a solvent. In certain embodiments, a Lewisacid of the carbonylation catalyst is of formula IIIc and L is anethereal solvent. In certain embodiments, a Lewis acid of thecarbonylation catalyst is of formula IIIc and each L is THF. In certainembodiments, wherein a Lewis acid of the carbonylation catalyst is offormula IIIc, M is Ti. In certain embodiments, wherein a Lewis acid ofthe carbonylation catalyst is of formula Inc, the transition metalcomplex is [Co(CO)₄]⁻.

In certain embodiments, a carbonylation catalyst is of formula IIc(i):

Reaction Conditions

Turning now to a more detailed description of the invention, it has beenfound that the catalyst described above can be used to successfullytransform epoxides into 3-hydroxy-δ-lactones exclusively, with no orvery little formation of the competing β-lactone product. In variousembodiments, certain reaction conditions may affect the outcome (e.g.,the yield) of these processes including, but not limited to: thepresence of a solvent, the concentration of the substrate, the amount ofcatalyst present, and the pressure and temperature at which the reactionis performed.

In certain embodiments, the solvent used will fully dissolve the epoxidesubstrate and provide a reaction mixture in which the catalyst employedis at least partially soluble. Suitable solvents may include ethers,ketones, aromatic hydrocarbons, halocarbons, esters, nitriles, and somealcohols. For example, without limitation, a suitable solvent mayinclude: 1,4-dioxane; tetrahydrofuran; tetrahydropyran; dimethoxyethane;glyme; diethyl ether; t-butyl methyl ether; 2,5-dimethyltetrahydrofuran; ethyl acetate; propyl acetate; butyl acetate; acetone;2-butanone; cyclohexanone; toluene; acetonitrile; and difluorobenzene.Mixtures of two or more of the above solvents are also useful, and insome cases may be preferred to a single solvent.

In certain embodiments, the solvent is a polar aprotic solvent such asdimethoxyethane. In some embodiments, the amount of solvent used is suchthat the concentration of the reaction is between approximately 0.1 Mand approximately 10 M. In some embodiments, the concentration isbetween approximately 0.1 M and approximately 5 M. In some embodiments,the concentration is between approximately 0.1 M and approximately 2.5M. In some embodiments, the concentration is between approximately 0.5 Mand approximately 5 M. In some embodiments, the concentration is betweenapproximately 0.5 M and approximately 1.5 M. In certain embodiments, theconcentration is approximately 1.0 M.

The reaction of the present invention is conducted under a carbonmonoxide atmosphere at a pressure from about 40 psi, to about 2500 psi.For example the carbon monoxide pressure may range from about 80 psi toabout 2000 psi or from about 500 psi to about 1000 psi. In certainembodiments, the carbon monoxide pressure is approximately 800 psi.Optionally, the atmosphere under which the reaction is conducted caninclude other gasses. Such other gasses can include, for example,hydrogen, methane, nitrogen, carbon dioxide, air, and trace amounts ofsteam. The present invention also specifically encompasses processes inwhich other carbon monoxide-containing gas streams provide theatmosphere under which the reaction is conducted, the use of syngas,wood gas, or other carbon monoxide-containing industrial gas streams arespecifically included.

Turning next to the effect of temperature, in certain embodiments thereaction temperature was found to affect the rate and outcome ofprocesses of the invention. At higher temperatures the reaction mayproceed more quickly than at lower temperatures, but the propensity toform reaction by-products may increase. In some cases therefore, theoptimal temperature will be dependent upon the pressure at which thereaction is conducted. When the reaction is conducted at a carbonmonoxide pressure of about 800 psi, the optimal temperature ranges fromapproximately 0° C. to approximately 200° C. In some embodiments, thetemperature ranges from approximately 5° C. and approximately 150° C. Insome embodiments, the temperature ranges from approximately 10° C. toapproximately 100° C. In certain embodiments, the temperature rangesfrom approximately 25° C. and approximately 75° C. In some embodiments,the optimal reaction temperature is approximately 60° C. In someembodiments, the optimal reaction temperature is approximately 70° C. Insome embodiments, the optimal reaction temperature is approximately 80°C.

The reaction time of the inventive method ranges from approximately 1minute to approximately 1 week. In some embodiments, the reaction timeranges from approximately 0.5 hour to approximately 140 hours. In someembodiments, the reaction time ranges from approximately 1.0 hour toapproximately 96 hours. In some embodiments, the reaction time rangesfrom approximately 1.0 hour to approximately 72 hours. In someembodiments, the reaction time ranges from approximately 6 hours toapproximately 72 hours. In some embodiments, the reaction time rangesfrom approximately 12 hours to approximately 72 hours. In someembodiments, the reaction time ranges from approximately 12 hours toapproximately 48 hours. In some embodiments, the reaction time rangesfrom approximately 12 hours to approximately 36 hours. In certainembodiments, the reaction time is approximately 6 hours. In certainembodiments, the reaction time is approximately 12 hours. In certainembodiments, the reaction time is approximately 18 hours. In certainembodiments, the reaction time is approximately 24 hours. In certainembodiments, the reaction time is approximately 48 hours.

Turning next to the catalysts, the catalyst is preferably present in anamount sufficient to allow the reaction process to be completed in aconvenient time interval. In real terms this can require catalystloadings ranging from about 0.0001 mole percent to about 20 mole percentbased on the epoxide substrate. In certain embodiments, the catalystloading can range from about 0.001 mole percent to about 20 molepercent. In certain embodiments, the catalyst loading can range fromabout 0.001 mole percent to about 10 mole percent. In certainembodiments, the catalyst loading can range from about 0.01 mole percentto about 10 mole percent. In certain embodiments, the catalyst loadingcan range from about 0.1 mole percent to about 10 mole percent. Incertain embodiments, the catalyst loading can range from about 0.1 molepercent to about 5 mole percent. In certain embodiments, the catalystloading can range from about 0.5 mole percent to about 2.5 mole percent.In certain embodiments, the catalyst loading can range from about 1.0mole percent to about 2.0 mole percent. In certain embodiments, thecatalyst loading is about 2.0 mole percent.

The catalysts of the instant invention can be prepared in any one of themethods known to those of ordinary skill in the art. In certainembodiments wherein the catalyst is HCo(CO)₄, preparation of thecatalyst proceeds by treating Ph₃Si(CO)₄ with p-toluenesulfonic acid(PTSA) in a suitable solvent (e.g., dimethoxyethane [DME]).

DEFINITIONS

Alkenyl: The term ‘alkenyl’ as used herein means a branched orunbranched, mono- or poly-unsaturated hydrocarbon radical having one ormore carbon-carbon double bonds. Each double bond can be substituted orunsubstituted, and can have cis or trans stereochemistry. The doublebonds of polyunsaturated radicals can be conjugated or unconjugated andcan include allenes. The term is also meant to encompass alkenyl groupswhere one or more hydrogen atoms are replaced by a halogen atom.Examples of alkenyl groups include, but are not limited to: vinyl,allyl, isoprenyl, cis-hex-3-enyl, trans-hex-3-enyl, trans, transbutane-1,3-dienyl, 3,3 dimethyl allenyl, 4-methyl hex-1-enyl,cis-but-2-enyl, and 4-methyl-1-hexenyl.

Alkyl: The term ‘alkyl’ as used herein means a branched or straightchain saturated hydrocarbon radical. The term is also meant to encompassalkyl groups where one or more hydrogen atoms are replaced by a halogenatom. Examples of alkyl groups include, but are not limited to: methyl,ethyl, n-propyl, n-hexyl, isobutyl, t-butyl, thexyl, 2-methyl pentyl,dichloromethyl, fluoromethyl, trifluoromethyl, pentafluoropropyl, andn-decyl.

Alkynyl: The term ‘alkynyl’ as used herein means a branched orunbranched, mono- or poly-unsaturated hydrocarbon radical having one ormore carbon-carbon triple bonds. The term is also meant to encompassalkenyl groups where one or more hydrogen atoms are replaced by ahalogen atom. Examples of alkynes include, but are not limited topropargyl, 2-butynyl, 5-hexynyl, and 2,2-dimethyl-3-butynyl.

Carbocycle: The term ‘carbocycle’ as used herein means a saturated,unsaturated or aromatic ring system where all atoms comprising thering(s) are carbon atoms. The term includes structures having more thanone ring, such as fused ring systems, bridged ring systems andspirocycles. Carbocycles can include the carbon atoms of keto, imine,and oxime groups and can be substituted with one or more additionalgroups. If a specific number of carbons is recited with a specificappearance of the term carbocycle (e.g., ‘up to C₁₂ carbocycle’), it isto be understood that the number refers only to those carbon atomscomprising the ring system and does not include any carbon atoms insubstituents that may optionally be attached thereto.

Where a substituent is defined to encompass alkenyl or alkynylsubstituents, it is to be understood that moieties having bothcarbon-carbon double bonds and carbon-carbon triple bonds (e.g., enynes)are also encompassed.

Heterocycle: The term ‘heterocycle’ as used herein means a saturated,unsaturated, or aromatic ring structure where one or more atoms in thering is a heteroatom. The term includes structures having more than onering, such as fused ring systems, bridged ring systems and spirocycles.The rings can also include the carbon atoms of keto, imine, and oximegroups and can be substituted with one or more additional groups. If aspecific number of carbons is recited with a specific appearance of theterm heterocycle (e.g., ‘up to C₁₂ heterocycle’), it is to be understoodthat the number refers only to those carbon atoms comprising the ringsystem and does not include any carbon atoms in substituents that mayoptionally be attached thereto.

The present invention will be more specifically illustrated withreference to the following examples. Many of these examples aredescribed in Rowley et al., J. Am. Chem. Soc. 2007, (129) 4948-4960 andin the supporting information published therewith. The entirety of thispublication and its supporting information are hereby incorporatedherein by reference.

EXAMPLES General Considerations

All manipulations of air- and/or water-sensitive compounds were carriedout using standard Schlenk line techniques or in an MBraun Unilab dryboxunder an atmosphere of dry nitrogen. NMR spectra were recorded usingVarian Mercury or Inova spectrometers (¹H NMR, 300 MHz; ¹³C NMR, 75 MHzand 125 MHz; ¹⁹F NMR, 470 MHz) and referenced against residual solventshifts for ¹H and ¹³C NMR and hexafluorobenzene for ¹⁹F NMR spectra. ¹HNMR and ¹³C NMR spectra of the product ³HLs were identified bycomparison to published spectra for 4-hydroxy-6-pentyl-δ-lactone (7),¹4-hydroxy-6-methyl-δ-lactone (7a),² 4-hydroxy-6-phenyl-5-lactone (7c),³6-ethyl-4-hydroxy-6-methyl-δ-lactone (7d),⁴6-(tert-butyldimethylsiloxymethyl)-4-hydroxy-δ-lactone (7i),⁵ and6-chloromethyl-4-hydroxy-δ-lactone (7j).⁶ All epoxides and lactones wereprepared as racemic mixtures of diastereomers, except where noted. Massspectra were acquired using a JEOL GCMate II mass spectrometer operatingat 3000 resolving power for high resolution measurements in positive ionmode and an electron ionization potential of 70 eV. Samples wereintroduced via a GC inlet using an Agilent HP 6890N GC equipped with a30 m (0.25 μm i.d.) HP-5 ms capillary GC column. The carrier gas washelium with a flow rate of 1 ml/min. Samples were introduced into the GCusing a split/splitless injector at 230° C. with a split ratio of 10:1.Lactones 7b, (R,R)-7b, 7g, and 7h were analyzed using direct injectioninto the mass spectrometer to avoid dehydration in the GC. Opticalrotations were measured on a Perkin-Elmer 241 digital polarimeter andare reported in the following format: [α]^(T) _(D)r (c, solvent), whereT=temperature in ° C., D refers to the sodium D line (589 nm), r is themeasured rotation, and c is the concentration in g/dL. IR spectra weremeasured on a Mattson RS-10500 Research Series FTIR. In situ IR datawere collected using a 100-mL Parr reactor modified for use with aMettler-Toledo ReactIR 4000 Reaction Analysis System fitted with aSentinel DiComp high-pressure probe, and analyzed with ReactIR softwareversion 2.21. All other carbonylation reactions were performed in acustom-built six-well reactor⁷ heated on a hot plate and equipped withmagnetic stir bars. All carbonylation reactions were performed in awell-ventilated fume hood equipped with a CO sensor, as carbon monoxideis a highly toxic gas.

Materials

Tetrahydrofuran (THF) was dried over a column of alumina and degassed bysparging with dry nitrogen. Diethyl ether was dried and deoxygenated oncolumns of alumina and Q5 copper, respectively. 1,2-Dimethoxyethane(DME) was transferred under reduced pressure from sodium/benzophenone.1,2-Epoxyhexane, 1,1,2,2-tetrafluoroethylglycidyl ether,epichlorohydrin, tert-butyldimethylsilylglycidyl ether, hexanal,cyclopentanone, cyclododecanone, 4-pentene-2-ol, 4-phenyl-1-buten-4-ol,allyl magnesium bromide, vinyl magnesium bromide, copper iodide,meta-chloroperbenzoic acid (mCPBA), and peracetic acid were purchasedfrom Aldrich and used as received. Sodium acetate (anhydrous),2-butanone, and acetic acid were purchased from Mallinckrodt.1,6-Heptadien-4-ol was purchased from Acros. para-Toluene sulfonic acidwas purchased from Fischer. Dicobalt octacarbonyl and(1R,2R)-(−)-1,2-cyclohexanediamino-N,N′-bis(3,5-di-t-butylsalicylidene)cobaltwere purchased from Strem. Research-grade carbon monoxide (99.99% min.)was purchased from Matheson and used without purification. Catalysts 1,⁸2,⁹ 3,¹⁰ 4,¹¹ and 5¹² and Ph₃SiCo(CO)₄ ¹³ were prepared according toliterature procedures. 4-Hydroxy-1,2-epoxynonane (6),¹⁴4-hydroxy-1,2-epoxypentane (6a),¹⁵ 4-hydroxy-4-phenyl epoxybutane(6c),¹⁶ 4-hydroxy-4-methyl-1,2-epoxyhexane (6d),¹⁷1-(2,3-epoxypropyl)-cyclopentan-1-ol (6e),¹⁸ and4-hydroxy-1,6-heptadiene monoepoxide (6g)¹⁹ were synthesized in ananalogous manner to those in the Experimental Section and characterizedby comparison to literature reports. Solid epoxides were dried undervacuum and liquid epoxides were dried over activated 4 Å molecularsieves and degassed three times by freeze-pump-thaw cycles.

The following examples describe exemplary catalyst/solvent combinationswhich we have shown can be used to effect high yield doublecarbonylation of epoxides. It is to be understood that thesecombinations are exemplary and that, in view of the representativeteachings that are provided in this disclosure, those skilled in the artwill be able to identify a variety of alternative combinations.

Example 1 Convergent Synthesis of Homoglycidols

This example describes the synthesis of various glycidols fromcommercially available epoxides and aldehydes (Scheme shown below).

4-Hydroxy-1,2-epoxyoctane (6b)

Copper iodide (0.79 g, 4.1 mmol) was added to a 250-mL oven-driedthree-neck round-bottom flask and diluted with 40 mL dry THF. Vinylmagnesium bromide (1.0 M solution in diethyl ether, 50 mL, 50 mmol) wasslowly added to the flask and stirred for 20 minutes. The flask was thencooled to −78° C. and a solution of 1,2-epoxyhexane (4.15 g, 41 mmol) in30 mL THF was slowly added via an addition funnel under nitrogen. Thereaction was slowly warmed to room temperature over the course of 16hours, then cooled to 0° C. and quenched with saturated ammoniumchloride. The aqueous layer was extracted with diethyl ether and thecombined organic layers were evaporated in vacuo.

The crude homoallylic alcohol was epoxidized by diluting in CH₂Cl₂ (˜1 Msolution) and slowly adding mCPBA (11 g, 66 mmol) to the solution at 0°C. The reaction was warmed to room temperature and stirred for 18 hours,at which time it was cooled back to 0° C. and quenched with 10% sodiumbisulfate (aq). The organic layer was extracted twice with sat. NaHCO₃(aq) and sat. NaCl (aq) and dried over MgSO₄. Solvent was removed invacuo and the crude epoxide was distilled at 65° C. under vacuum toafford pure 6b (1.8 g, 34%, syn:anti ca. 50:50) as a racemic mixture ofdiastereomers. ¹H NMR (δ, CDCl₃, 300 MHz) 0.85 (t, ³J=6.5 Hz, 6H),1.18-1.59 (m, 12H), 1.70-1.82 (m, 2H), 2.38-2.58 (m, 4H), 2.70-2.80 (m,2H), 3.00-3.15 (m, 2H), 3.69-3.87 (m, 2H); ¹³C NMR (8, CDCl₃, 75 MHz)14.15, 22.78, 27.79, 27.85, 37.25, 37.43, 39.35, 39.87, 46.75, 47.12,50.38, 50.72, 69.30, 70.44.

1-(2,3-Epoxypropyl)-cyclododecan-1-ol (6f)

An oven-dried 500-mL three-neck round-bottom flask was charged withcyclododecanone (6.00 g, 32.9 mmol) and 50 mL dry THF. A 100-mL additionfunnel with allyl magnesium bromide (1.0 M solution in THF, 36.2 mL,36.2 mmol) was attached and the flask was cooled in an ice bath for 10minutes. The Grignard was slowly dripped in over the course of 30minutes while stirring at 0° C. under nitrogen. After addition, the icebath was removed and the reaction mixture was stirred for 4 hours atroom temperature under nitrogen. Excess Grignard was quenched by slowlyadding water to the reaction mixture cooled to 0° C., and the productwas extracted three times with diethyl ether. The organic layer wasdried over Na₂SO₄ and solvent was removed under vacuum to obtain thehomoallylic alcohol that was used without further purification.

The epoxide was synthesized by addition of peracetic acid (32% solutionin dilute acetic acid, 16.6 ml, 79.0 mmol) to a CH₂Cl₂ solution of crudehomoallylic alcohol and sodium acetate (4.05 g, 49.4 mmol) at 0° C.; thereaction was stirred at room temperature for 18 h. Excess peroxide wasquenched with a 10% aqueous solution of sodium bisulfite and the organiclayer was washed 3 times with water and brine. Evaporation of solventyielded crude epoxide which was recrystallized from hot hexanes (5 mL)to afford colorless crystals of 6f (5.03 g, 64%) as a racemic mixture.¹H NMR (δ, CDCl₃, 300 MHz) 1.22-1.86 (m, 25H), 2.48 (dd, ³J=2.8 Hz,²J=5.1 Hz, 1H), 2.80 (dd, ³J=3.9 Hz, ²J=5.1 Hz, 1H), 3.19 (dddd, ³J=2.7Hz, ³J=3.0 Hz, ³J=4.2 Hz, ³J=5.1 Hz, 1H); ¹³C NMR (δ, CDCl₃, 75 MHz)19.59, 19.80, 22.24, 22.71, 26.18, 26.56, 26.60, 34.91, 35.05, 43.25,46.99, 49.24, 75.47. Note: Two peaks were not visible due to degeneracy.

5-(1,1,2,2-Tetrafluoroethoxy)-4-hydroxy-1,2-epoxypentane (6h)

Copper iodide (0.52 g, 2.7 mmol) was added to a 250-mL oven-driedthree-neck round-bottom flask and diluted with 25 mL dry THF. Vinylmagnesium bromide (1.0 M solution in diethyl ether, 27 mL, 27 mmol) wasslowly added to the flask and stirred for 20 minutes. The flask was thencooled to −78° C. and a solution of 1,1,2,2-tetrafluoroethyl glycidylether (5.2 g, 30 mmol) in 20 mL THF was slowly added via an additionfunnel under nitrogen. The reaction was slowly warmed to roomtemperature over the course of 16 hours, then cooled to 0° C. andquenched with saturated ammonium chloride. The aqueous layer wasextracted with diethyl ether and the combined organic layers wereevaporated in vacuo.

The crude homoallylic alcohol was epoxidized by diluting in CH₂Cl₂ (˜1 Msolution) and slowly adding mCPBA (8.5 g, 49 mmol) to the solution at 0°C. The reaction was warmed to room temperature and stirred for 18 hours,at which time it was cooled back to 0° C. and quenched with 10% sodiumbisulfate (aq). The organic layer was extracted twice with sat. NaHCO₃(aq) and sat. NaCl (aq) and dried over MgSO₄. Solvent was removed invacuo and the crude epoxide was distilled at 60° C. under vacuum toafford pure 6h (2.2 g, 33%, syn: anti ca. 50:50) as a racemic mixture ofdiastereomers. NMR (8, CDCl₃, 300 MHz) 1.49-1.65 (m, 2H), 1.94-2.05 (m,1H), 2.40 (d, ³J=3.8 Hz, 1H), 2.55 (dd, ³J=2.7 Hz, ³J=4.8 Hz, 1H), 2.61(dd, ³J=2.7 Hz, ³J=4.8 Hz, 1H), 2.82 (dd, ³J=4.1 Hz, ³J=4.7 Hz, 1H),2.86 (dd, ³J=4.1 Hz, ³J=4.7 Hz, 1H), 3.10-3.20 (m, 2H), 3.91 (dd, ³J=7.0Hz, ²J=10.0 Hz, 1H), 4.00 (pseudo-d, 2H), 4.04 (dd, ³J=3.9 Hz, ²J=10.0Hz, 1H), 4.07-4.20 (m, 2H), 5.74 (tt, ³J=2.5 Hz, ²J=53.3 Hz, 2H); ¹³CNMR (5, CDCl₃, 75 MHz) δ5.55, 35.82, 46.77, 47.25, 49.60, 49.72, 67.54,67.91 (t, ³J=4.6 Hz), 68.14, 68.15 (t, ³J=4.6 Hz), 107.87 (tt, ²J=42 Hz,J=249 Hz) Note: The CF₂ carbon was not definitively identified.

5-(tert-Butyldimethylsilyloxy)-4-hydroxy-1,2-epoxypentane (6i)

Copper iodide (0.36 g, 1.9 mmol) was added to a 250-mL oven-driedthree-neck round-bottom flask and diluted with 20 mL dry THF. Vinylmagnesium bromide (1.0 M solution in diethyl ether, 23 mL, 23 mmol) wasslowly added to the flask and stirred for 20 minutes. The flask was thencooled to −78° C. and a solution of tert-butyldimethylsilyl glycidylether (3.6 g, 19 mmol) in 10 mL THF was slowly added via an additionfunnel under nitrogen. The reaction was slowly warmed to roomtemperature over the course of 16 hours, then cooled to 0° C. andquenched with sat. NH₄Cl (aq). The aqueous layer was extracted withdiethyl ether and the combined organic layers were evaporated in vacuo.

The epoxide was synthesized by addition of peracetic acid (32% solutionin dilute acetic acid, 9.6 mL, 46 mmol) to a CH₂Cl₂ solution of crudehomoallylic alcohol and sodium acetate (2.3 g, 28 mmol) at 0° C.; thereaction was stirred at room temperature for 18 h. Excess peroxide wasquenched with 10% sodium bisulfate (aq) and the organic layer was washed3 times with water and brine. Evaporation of solvent yielded crudeepoxide which was purified by column chromatography with 30% ethylacetate in hexanes to afford 6i (2.5 g, 58%, syn:anti ca. 50:50) as aracemic mixture of diastereomers. ¹H NMR (δ, CDCl₃, 300 MHz) 0.035 (s,12H), 0.86 (s, 18H), 1.37-1.83 (m, 4H), 2.46-2.51 (m, 2H), 2.63 (d,³J=3.6 Hz, 1H), 2.67 (d, ³J=3.6 Hz, 1H), 2.73 (t, ³J=4.8, 1H), 2.77 (t,³J=4.8 Hz, 1H), 3.02-3.12 (m, 2H), 3.37-3.66 (m, 4H), 3.75-3.90 (m, 2H);¹³C NMR (8, CDCl₃, 75 MHz) −5.28, −5.24, 18.40, 25.99, 35.83, 36.16,46.83, 47.32, 49.84, 49.94, 66.91, 67.23, 69.88, 69.98.

5-Chloro-4-hydroxy-1,2-epoxypentane (6j)

Copper iodide (2.3 g, 12 mmol) was added to a 500-mL oven-driedthree-neck round-bottom flask and diluted with 100 mL dry THF.Epicholorohydrin (12 g, 130 mmol) was added to the flask which wasequipped with an addition funnel and cooled to −78° C. Vinyl magnesiumbromide (1.0 M solution in diethyl ether, 120 mL, 120 mmol) was slowlyadded to the flask and stirred for 30 minutes, then warmed to roomtemperature and stirred for 16 hours. The reaction was cooled to 0° C.and quenched with sat. NH₄Cl (aq). The organic layer was pushed througha plug of silica to remove magnesium salts and excess epichlorohydrinwas removed in vacuo.

The homoallylic alcohol was epoxidized with peracetic acid as in 61. Thecrude epoxide was purified by column chromatography using 30% ethylacetate in hexanes to afford 6j (2.5 g, 15%, syn:anti ca. 50:50) as aracemic mixture of diastereomers. ¹H NMR (8, CDCl₃, 300 MHz) 1.43-1.69(m, 2H), 1.87-2.00 (m, 2H), 2.49 (dd, ³J=2.7 Hz, 2J=4.8 Hz, 1H), 2.53(dd, ³J=3.0 Hz, ²J=4.8 Hz, 1H), 2.75 (t, ³J=4.5 Hz, 1H), 2.79 (t, ³J=4.5Hz, 1H), 3.02-3.13 (m, 2H), 3.09 (d, ³J=4.8, 1H), 3.16 (d, ³J=4.8 Hz,1H), 3.41-3.63 (m, 4H), 3.93-4.07 (m, 2H); ¹³C NMR (δ, CDCl₃, 75 MHz)δ6.83, 36.95, 46.67, 47.28, 49.56, 49.66, 49.69, 49.83, 69.35, 69.71.

(2R,4R)-4-Hydroxy-1,2-epoxyoctane ((R,R)-6b)

(R)-1,2-Epoxyhexane was prepared as reported by Jacobsen and coworkers(Schaus, et al., J. Am. Chem. Soc. 2002, 124, 1307-1315). Ring openingof the optically pure epoxide by vinyl magnesium bromide followed byepoxidation with mCPBA were performed in an analogous manner as 6h togive a 1:1 mixture of diastereomers. The diastereomers were resolvedusing Jacobsen HKR conditions. The epoxide (2.67 g, 18.5 mmol) wasdiluted in 2.5 mL THF. To this solution was added(1R,2R)-(−)-1,2-cyclohexanediamino-N,N′-bis(3,5-di-tbutylsalicylidene)cobalt(56.2 mg, 0.93 mmol) and glacial acetic acid (21.2 μL, 0.37 mmol). Thesolution was cooled to 0° C. and water (183 μL 10.2 mmol) was addeddropwise. After stirring at room temperature for 24 hours, THF wasremoved in vacuo and the residue was distilled under vacuum at 65° C. toafford (R,R)-6b (1.18 g, 13% from racemic 1,2-epoxyhexane, >99:1syn:anti) as a colorless oil. ¹H NMR (δ, CDCl₃, 300 MHz) 0.85 (t, ³J=6.9Hz, 3H), 1.17-1.81 (m, 8H), 2.42-2.49 (m, 1H), 2.47 (d, ³J=4.2 Hz, 1H),2.72 (t, ³J=4.2 Hz, 1H), 2.99-3.07 (m, 1H), 3.74-3.86 (m, 1H); ¹³C NMR(δ, CDCl₃, 75 MHz) 14.13, 22.75, 27.77, 37.22, 39.84, 46.73, 50.69,70.38.

Example 2 Preparation of HCo(CO)₄

This procedure was adapted from a similar synthesis of HCo(CO)₄ (Byrneet al. Manuscript in Preparation). In the glove box, Ph₃SiCo(CO)₄ (0.12mmol) and p-toluenesulfonic acid (0.12 mmol) were weighed into separateflame-dried vials. DME (6.0 mL) was divided evenly into each vial tocompletely dissolve the catalyst components. The two solutions werecombined to form a colorless solution of HCo(CO)₄ (0.05 M in DME) whichwas used immediately. Note: HCo(CO)₄ must be used immediately afterpreparation to ensure reproducible catalytic activity.

Example 3 Catalyst Screening for 3HL Formation

Table 1 illustrates initial results to carbonylate4-hydroxy-1,2-epoxynonane (6) to d-lactone (7) using known epoxidecarbonylation catalysts. Reactions using chromium catalysts 1 and 3afforded largely the β-lactone product, whereas aluminum catalysts 2 and4, and titanium catalyst 5 led to preferential formation of δ-lactone.Notably, HCo(CO)₄ led to virtually exclusive formation of the δ-lactone.

TABLE 1 Catalyst Screening for 3HL Formation

conversion^(a) (%) δ-lactone β-lactone entry catalyst (7) (8) 1 1 16 842 2 73 27 3 3 33 67 4 4 58 42 5 5 83 17 6 Co₂(CO)₈ 67 33 7 HCo(CO)₄^(b) >99  ND^(c) ^(a)Conversions determined by ¹H NMR spectroscopy;diastereomeric ratios of 6, 7, and 8 ca. 1:1. ^(b)Prepared in situ; seesupporting information for details ^(c)ND = Not Detected.

Example 4 Carbonylation of Homoglycidols

In a custom-built, six-well, high pressure stainless steel reactor, sixoven-dried vials (8 mL) were charged with epoxide (1.0 mmol) andmagnetic stir bars. Freshly prepared HCo(CO)₄ solution (1.0 mL, 0.05 Min DME) was transferred to each vial via syringe. The reactor was thensealed, pressured to 800 psi CO, and heated at 60° C. for 24 hours whilestirring. After the reaction time, the reactor was cooled in dry ice for10 minutes and the wells were vented in a well-ventilated fume hood.Crude ¹H NMR spectra were obtained by removing an aliquot of reactionmixture and passing it through a plug of silica with CDCl₃. Reactionsthat cleanly produced δ-lactone were purified by chromatography. Thecrude reaction mixture was concentrated to an oil under vacuum. Thiscrude product was passed through silica gel, first using 30% ethylacetate in hexanes to remove catalyst residue, then with 70% ethylacetate in hexanes to elute the δ-lactone product. On a small scale, theisolated 3HLs were sometimes contaminated with small amounts (<5%) ofcatalyst residue. The contamination was most dramatic with thealkyl-substituted homoglycidols (7-7b), leading to lower isolatedyields. The product 3HL was obtained by removing solvent in vacuo andanalyzed by comparison to literature reports, or fully characterized inthe case of unreported compounds.

Example 5 Optimization of Carbonylation Conditions

Using the above general procedure for homoglycidol carbonylation byHCo(CO)₄, CO pressure, temperature, catalyst loading, and reaction timewere varied to determine the optimal conditions (Table S1).

TABLE S1 Optimization of Carbonylation conditions.

CO Tempera- Conver- Epox- Pressure Time ture sion^(a) Entry ide:Catalyst(psi) (h) (° C.) (%) 1  20:1 100 48 23 47 2  20:1 800  6 60 99 3  20:1800  6 80  99^(b) 4  50:1 800 24 60 99 5 100:1 800 24 60 30 6 200:1 80024 60 NR^(c) ^(a)Conversions determined by ¹H NMR spectroscopy.^(b)Product contaminated with unknown impurities. ^(c)NR = No Reaction;only starting material detected.

Example 6 Synthesis of 3HLs Using HCo(CO)₄

Once reaction conditions were optimized for efficient δ-lactoneformation, a variety of substituted homoglycidols were carbonylated(Table 2). Both alkyl- and aryl-substituted homoglycidols werecarbonylated cleanly to 3HLs. Disubstituted homoglycidols (entries 4-6)produced 7d and the spiro 3HLs 7e and 7f; however, a small amount ofβ-lactone was also formed in these carbonylations.

TABLE 2 Synthesis of 3HLs using HCo(CO)₄

epoxide entry R R′ δ-lactone yield^(a) (%) 1 Me H 6a 7a 73 2 ^(n)Bu H 6b7b 60 3 Ph H 6c 7c 81 4 Me Et 6d 7d  58^(b) 5

 67^(c) 6

 75^(c)  7^(d)

76  8^(d)

92 9

52 10 

81 ^(a)Yield of isolated product. ^(b)6% β-Lactone formed. ^(c)4%β-Lactone formed. ^(d)5 mol % Catalyst used.

Example 7 Carbonylation of Enantiopure Homoglycidol (R,R)-6b withRetention of Stereochemistry

The ability to control the stereochemical outcome of the carbonylationis of great importance for any synthetic application. To test whether ornot this method affords retention of stereochemistry, (R,R)-6b wascarbonylated under standard conditions as shown below.

Analysis by ¹H and ¹³C NMR spectroscopy indicated the trans diastereomerwas formed exclusively, and optical rotation established the product asthe (3R,5R) isomer. Thus, the carbonylation occurs with retention ofboth stereocenters.

Example 8 Carbonylation of 4-hydroxy-1,2-epoxynonane (6) monitored by insitu IR spectroscopy

The adapted Parr reactor was dried under vacuum overnight and broughtinto the glove box. A solution of 6 (0.79 g, 5.0 mmol) in 5.0 mL DME wasdrawn into a 10 mL glass syringe. Another solution containing HCo(CO)₄(0.1 mmol in 5.0 mL DME) was drawn into a separate glass syringe. Theneedles from each syringe were inserted through a septum covering theinjection port of the reactor. The reactor was removed from the glovebox, connected to the ReactIR, and a background spectrum was recorded.Following the background, both the epoxide and catalyst solutions wereinjected into the reactor, which was then pressured to 800 psi with CO.While IR spectra were recorded every two minutes, the reactor was heatedto 60° C. using a heating jacket. The formation of δ-lactone (7) andβ-lactone (8) was monitored by the emergence of their carbonyl stretchesat 1744 cm⁻¹ and 1827 cm⁻¹, respectively (FIG. S1). The reaction wasallowed to proceed until the lactone absorbance was constant, at whichtime the reactor was cooled and vented. The crude reaction mixture wasanalyzed by ¹H NMR spectroscopy.

Isomerization of β-Lactone (8) Monitored by In Situ IR Spectroscopy.

A mixture of 7 and 8 was prepared under standard carbonylationconditions using catalyst 1 (see Table 1, entry 1). Catalyst residue wasremoved by passing the crude reaction mixture though a plug of silicawith CH₂Cl₂ and removing solvent in vacuo. The lactone mixture was thendried over activated 4 Å molecular sieves and degassed three times byfreeze-pump-thaw cycles. The dried Parr reactor was connected to theReact-IR and a background spectrum was acquired. Next, 930 mg (5.0 mmol)of 7/8 in 5 mL DME was added to the reactor which was pressured to 800psi with CO. The reactor was heated to 60° C. while acquiring a spectrumevery minute until the absorbances (CO stretches measured at 1744 cm⁻¹and 1827 cm⁻¹ for δ-lactone and β-lactone, respectively) of the twolactones remained constant. The reactor was then carefully vented to 50psi CO and a solution of 0.1 mmol HCo(CO)₄ in 5 mL DME was added viasyringe through the injector port. The reactor was then repressured to800 psi CO and the absorbances of 7 and 8 were monitored by continuingto acquire IR spectra every minute. The profile of the IR spectra isshown in FIG. S2. Since no isomerization of 8 to 7 is observed under thereaction conditions, 8 is eliminated as a possible intermediate in thecarbonylation of 6 to 7.

REFERENCES

-   (1) Gogoi, S.; Barua, N. C.; Kalita, B. Tetrahedron Lett. 2004, 45,    5577-5579.-   (2) Le Sann, C.; Muñoz, D. M.; Saunders, N.; Simpson, T. J.;    Smith, D. I.; Soulas, F.; Watts, P.; Willis, C. L. Org. Biomol.    Chem. 2005, 3, 1719-1728.-   (3) Aprile, C.; Gruttadauria, M.; Amato, M. E.; D'Anna, F.; Lo    Meo, P. Riela, S.; Noto, R. Tetrahedron, 2003, 59, 2241-2251.-   (4) Molander, G. A.; Etter, J. B.; Harring, L. S.; Thorel, P.- J. J.    Am. Chem. Soc. 1991, 113, 8036-8045.-   (5) MacKeith, R. A.; McCague, R.; Olivo, H. F.; Roberts, S. M.;    Taylor, S. J. C.; Xiong, H. Bioorg. Med. Chem. 1994, 2, 387-394.-   (6) Greenberg, W. A.; Varvak, A.; Hanson, S. R.; Wong, K.; Huang,    H.; Chen, P.; Burk, M. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,    5788-5793.-   (7) Getzler, Y. D. Y. L.; Kundnani, V.; Lobkovsky, E. B.;    Coates, G. W. J. Am. Chem. Soc. 2004, 126, 6842-6843.-   (8) Kramer, J. W.; Lobkovsky, E. B.; Coates, G. W. Org. Lett. 2006,    8, 3709-3712.-   (9) Getzler, Y. D. Y. L.; Mahadevan, V.; Lobkovsky, E. B.;    Coates, G. W. J. Am. Chem. Soc. 2002, 124, 1174-1175.-   (10) Schmidt, J. A. R.; Mahadevan, V.; Getzler, Y. D. Y. L.;    Coates, G. W. Org. Lett. 2004, 6, 373-376.-   (11) Rowley, J. M.; Lobkovsky, E. B.; Coates, G. W. J. Am. Chem.    Soc. 2007, 129, 4948-4960.-   (12) Mahadevan, V.; Getzler, Y. D. Y. L.; Coates, G. W. Angew. Chem.    Int. Ed. 2002, 41, 2781-2784.-   (13) Harrod, J. F.; Chalk, A. J. J. Am. Chem. Soc. 1965, 87,    1133-1135.-   (14) Ishikawa, M.; Amaike, M.; Itoh, M.; Warita, Y.; Kitahara, T.    Biosci. Biotechnol. Biochem. 2003, 67, 2210-2214.-   (15) Brown, H. C.; Lynch, G. J. J. Org. Chem. 1981, 46, 930-939.-   (16) Banerjee, B.; Roy, S. C. Eur. J. Org. Chem. 2006, 489-497.-   (17) Murray, R. W.; Gu, H. J. Phys. Org. Chem. 1996, 9, 751-758.-   (18) Bats, J. P.; Moulines, J.; Leclercq, D. Tetrahedron 1982, 38,    2139-2146.-   (19) Palombi, L.; Bonadies, F.; Scettri, A. Tetrahedron 1997, 53,    11369-11376.-   (20) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.;    Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am.    Chem. Soc. 2002, 124, 1307-1315.-   (21) Byrne, C. M.; Church, T. L.; Kramer, J. W.; Lobkovsky, E. B.;    Coates, G. W. Manuscript in Preparation.-   (23) The R,R diastereomer of 6-pentyl-4-hydroxy-δ-lactone has been    reported: [α]²³ _(D)+32.1 (c=0.92, CHCl₃). Romeyke, Y.; Keller, M.;    Kluge, H.; Grabley, S.; Hammann, P. Tetrahedron 1991, 47, 3335-3339.    The optical rotation of (R,R)-7b is in line with the literature    report for the analogous compound in both magnitude and direction of    rotation.

Other Embodiments

Other embodiments of the invention will be apparent to those skilled inthe art from a consideration of the specification or practice of theinvention disclosed herein. It is intended that the specification andExamples be considered as exemplary only, with the true scope of theinvention being indicated by the following claims. The contents of anyreference that is referred to herein are hereby incorporated byreference in their entirety.

We claim:
 1. A method comprising the steps of: reacting an epoxide offormula:

wherein: n is an integer between 0 and 3, inclusive; R_(a) and R_(b) areeach independently hydrogen; halogen; C₁ to C₂₀ alkyl; C₂ to C₂₀alkenyl; C₂ to C₂₀ alkynyl; up to a C₁₆ carbocycle; up to a C₁₆heterocycle; —C(R¹³)_(z)H_((3-z)); or a polymer chain; or R_(a) andR_(b) are taken together with intervening atoms to form one or moreoptionally substituted rings optionally containing one or moreheteroatoms, and either of R_(a) or R_(b) may optionally be furthersubstituted with one or more X groups; R_(c), R_(d), and each R groupare hydrogen; P′ is hydrogen; each occurrence of X is independentlyhalogen; a phosphorus-containing moiety, —OR¹⁰; —OC(O)R¹³; —OC(O)OR¹³;—OC(O)NR¹¹R¹²; —CN; —CNO; —C(O)R¹³; —C(O)OR¹³; —C(O)NR¹¹R¹²;—C(R¹³))_(z)H_((3-z)); —NR¹¹C(O)R¹⁰; —NR¹¹C(O)OR¹⁰; —NCO; —NR¹²SO₂R¹³;—S(O)_(x)R¹³; —S(O)₂NR¹¹R¹²; —NO₂; —N₃; —(CH₂)_(k)R¹⁴; —(CH₂)_(k)—Z—R¹⁴;and —(CH₂)_(k)—Z—(CH₂)_(m)—R¹⁴; R¹⁰ at each occurrence can beindependently selected from the group consisting of: hydrogen;—C(R¹³)_(z)H_((3-z)); C₁ to C₁₂ alkyl; C₂ to C₁₂ alkenyl; C₂ to C₁₂alkynyl; up to a C₁₂ carbocycle; up to a C₁₂ heterocycle; —S(O)₂R¹³;—Si(R¹⁵)₃; and a hydroxyl protecting group; R¹¹ and R¹² at eachoccurrence can be independently selected from the group consisting of:hydrogen; C₁ to C₁₂ alkyl; C₂ to C₁₂ alkenyl; C₂ to C₁₂ alkynyl; and—C(R¹³)_(z)H_((3-z)); R¹¹ and R¹²; when both present, can optionally betaken together with the atom to which they are attached to form anoptionally substituted 3- to 10-membered ring, optionally containing oneor more additional heteroatoms; R¹³ at each occurrence can beindependently selected from the group consisting of: hydrogen; halogen;C₁ to C₁₂ alkyl; C₂ to C₁₂ alkenyl; C₂ to C₁₂ alkynyl; up to a C₁₂carbocycle; or up to a C₁₂ heterocycle; R¹⁴ at each occurrence can beindependently selected from the group consisting of halogen; —OR¹⁰;—OC(O)R¹³; —OC(O)OR¹³; —OC(O)NR¹¹R¹²; —CN; —CNO; —C(R¹³)_(z)H_((3-z));—C(O)R¹³; —C(O)OR¹³; —C(O)NR¹¹R¹²; —NR¹¹C(O)R¹³; —NR¹¹C(O)OR¹⁰;—NR¹¹SO₂R¹³; —NCO; —N₃; —NO₂; —S(O)_(x)R¹³; —SO₂NR¹¹R¹²; up to a C₁₂heterocycle; and up to a C₁₂ carbocycle; R¹⁵ at each occurrence can beindependently selected from the group consisting of: C₁ to C₆ alkyl; C₂to C₆ alkenyl; C₂ to C₆ alkynyl; and up to C₁₂ substituted orunsubstituted carbocycle; Z is a divalent linker and can be selectedfrom the group consisting of: —(CH═CH)_(a)—; —(CH≡CH)_(a)—; —C(O)—;—C(═NOR¹¹)—; —C(═NNR¹¹R¹²)—; —O—; —N(R¹¹)—; —N(C(O)R¹³)—; —S(O)_(x); apolyether; and a polyamine; a can be 1, 2, 3, or 4; k can be an integerfrom 1 to 8 inclusive; m can be an integer from 1 to 8 inclusive; x canbe 0, 1, or 2; and z can be 1, 2, or 3; with carbon monoxide (CO) in thepresence of a catalytically effective amount of a catalyst of theformula:[Lewis acid]^(u+){[QT(CO)_(v)]^(s−)}^(t)  II wherein: Q is any ligand orset of ligands and need not be present; T is a metal selected from group7, 8, or 9 of the periodic table; s is an integer from 1 to 4 inclusive;t is a number such that t multiplied by s equals u; u is an integer from1 to 6 inclusive; v is an integer from 1 to 9 inclusive; and the Lewisacid is H+ or is of formula [M(L)_(b)]^(c+), wherein M is a transitionmetal or group 13 or 14 metal; L is a ligand and need not be present; bis an integer from 1 to 6, inclusive; and c is 1, 2, or 3; to produce acompound of the formula:


2. The method of claim 1, wherein the epoxide is of the formula:

wherein p is an integer between 1 and 4, inclusive.
 3. The method ofclaim 1, wherein the epoxide is of the formula:

wherein p is an integer between 1 and 4, inclusive.
 4. The method ofclaim 1, wherein the epoxide is of the formula:


5. The method of claim 1, wherein the epoxide is of the formula:

wherein m is an integer between 0 and 10, inclusive.
 6. The method ofclaim 1, wherein the epoxide is of the formula:


7. The method of claim 6, wherein X is a halogen.
 8. The method of claim6, wherein X is chlorine.
 9. The method of claim 1, wherein the epoxideis of the formula:


10. The method of claim 1, wherein the epoxide is of the formula:


11. The method of claim 10, wherein R¹⁰ is a suitable protecting groupor hydrogen.
 12. The method of claim 11, wherein R¹⁰ is a silylprotecting group.
 13. The method of claim 12, wherein R¹⁰ istert-butyldimethylsilyl.
 14. The method of claim 1, wherein the epoxideis of the formula:


15. The method of claim 1, wherein the epoxide is of the formula:


16. The method of claim 1, wherein the epoxide is of the formula:


17. The method of claim 1, wherein the epoxide is of the formula:


18. The method of claim 1, wherein T is cobalt.
 19. The method of claim1, wherein Q is absent.
 20. The method of claim 1, wherein v is
 4. 21.The method of claim 1, wherein the Lewis acid is H⁺.
 22. The method ofclaim 1, wherein the carbonylation catalyst is HCo(CO)₄.
 23. The methodof claim 1, wherein the Lewis acid is of formula IIIa:

wherein: R^(e) at each occurrence is independently selected from thegroup consisting of: hydrogen; C₁-C₁₂ alkyl; C₂-C₁₂ alkenyl; C₂-C₁₂alkynyl; aryl; heteroaryl; halogen; —OR¹⁰; —OC(O)R¹³; —OC(O)OR¹³;—OC(O)NR¹¹R¹²; —CN; —CNO; —C(O)R¹³; —C(R¹³)_(z)H_((3-z)); —C(O)OR¹³;—C(O)NR¹¹R¹²; —NR¹¹R¹²; —NR¹¹C(O)R¹⁰; —NR¹¹C(O)OR¹³; —NR¹¹SO₂R¹³; —NCO;—N₃; —NO₂; —S(O)_(x)R¹³; —SO₂NR¹¹R¹²; —C(R¹³)_(z)H_((3-z));—(CH₂)_(k)R¹⁴; —(CH₂)_(k)—Z—R¹⁶—; and —(CH₂)_(k)—Z—(CH₂)_(m)—R¹⁴, wheretwo or more R^(e) groups may optionally be taken together to form anoptionally substituted ring; and wherein M, L, R¹⁰, R¹¹, R¹², R¹³, R¹⁴,R¹⁶, Z, k, m, x, and z are as defined in claim
 1. 24. The method ofclaim 23, wherein M is Al.
 25. The method of claim 23, wherein the Lewisacid is of formula IIIa(ii):

wherein -Ph represents an optionally substituted phenyl group and L isas defined in claim
 1. 26. The method of claim 23, wherein thecarbonylation catalyst is of formula IIa(i):


27. The method of claim 1, wherein the Lewis acid is of formula IIIb:

wherein: R¹ and R^(1′) are independently selected from the groupconsisting of: hydrogen; C₁ to C₁₂ alkyl; C₂ to C₁₂ alkenyl; C₂ to C₁₂alkynyl; —C(R¹³)_(z)H_((3-z)); —(CH₂)_(k)R¹⁴; and —(CH₂)_(k)—Z—R¹⁴; R²,R^(2′), R³, and R^(3′) are independently selected from the groupconsisting of: (i) C₁-C₁₂ alkyl; (ii) C₂-C₁₂ alkenyl; (iii) C₂-C₁₂alkynyl; (iv) up to a C₁₂ carbocycle; (v) up to a C₁₂ heterocycle; (vi)—(CH₂)_(k)R¹⁴; (vii) R²⁰; and (viii) —C(R¹³)_(z)H_((3-z)), wherein eachof (i) through (v) may optionally be further substituted with one ormore R²⁰ groups; and where R² and R³, and R^(2′) and R^(3′) mayoptionally be taken together with the carbon atoms to which they areattached to form one or more rings which may in turn be substituted withone or more R²⁰ groups; R⁴ is selected from the group consisting of:

wherein X′ is a divalent linker selected from the group consisting of:—N(R¹¹)—; —O—; —S(O)_(x)—; —(CH₂)_(k)—; —C(O)—; —C(═NOR¹⁰)—;—C(R^(f))₂—; a polyether; a C₃ to C₈ substituted or unsubstitutedcarbocycle; and a C₁ to C₈ substituted or unsubstituted heterocycle;R^(e) is as defined above; R^(f) at each occurrence is independentlyselected from the group consisting of: (a) C₁-C₁₂ alkyl; (b) C₂-C₁₂alkenyl, (c) C₂-C₁₂ alkynyl; (e) up to a C₁₂ carbocycle, (f) up to a C₁₂heterocycle; (g) R²⁰; and (h) —C(R¹³)_(z)H_((3-z)); or wherein: two ormore R^(f) groups may be taken together with the carbon atoms to whichthey are attached to form one or more rings; or wherein when two R^(f)groups are attached to the same carbon atom, they may be taken togetherto form a moiety selected from the group consisting of: a 3- to8-membered spirocyclic ring; a carbonyl (C═O), an oxime (C═NOR¹⁰); ahydrazone (C═NNR¹¹R¹²); an imine (C═NR¹¹); and an alkenyl group(C═CR¹¹R¹²); R²⁰ at each occurrence is independently selected from thegroup consisting of: hydrogen; halogen; —OR¹⁰; —OC(O)R¹³; —OC(O)OR¹³;—OC(O)NR¹¹R¹²; —CN; —CNO; —C(O)R¹³; —C(O)OR¹³; —C(O)NR¹¹R¹²;—C(R¹³)_(z)H_((3-z)); —NR¹¹R¹²; —NR¹¹C(O)R¹⁰; —NR¹¹C(O)OR¹⁰; —NCO;—NR¹²SO₂R¹³; —S(O)_(x)R¹³; —S(O)₂NR¹¹R¹²; —NO₂; —N₃; —(CH₂)_(k)R¹⁴;—(CH₂)_(k)—Z—R¹⁶; and —(CH₂)_(k)—Z—(CH₂)_(m)—R¹⁴; and L, M, R¹⁰, R¹¹,R¹², R¹³, R¹⁴, R¹⁶, Z, k, m, x, and z are as defined in claim
 1. 28. Themethod of claim 27, wherein M is Al.
 29. The method of claim 27, whereinthe Lewis acid is of formula IIIb(i):

wherein M is Al and L is as defined in claim
 1. 30. The method of claim27, wherein the carbonylation catalyst is of formula IIb(ii):


31. The method of claim 1, wherein the Lewis acid is of formula IIIc:

wherein M and L are as defined in claim
 1. 32. The method of claim 31,wherein M is Ti.
 33. The method of claim 31, wherein the carbonylationcatalyst is of formula IIc(i):


34. The method of claim 1, wherein carbonylation proceeds with retentionof stereochemistry.
 35. A method comprising steps of: reacting anepoxide of formula S-Ia′:

wherein:

is a single bond; P′ is hydrogen; Q′ is selected from the groupconsisting of: hydrogen; halogen; (a) C₁ to C₂₀ alkyl; (b) C₂ to C₂₀alkenyl; (c) C₂ to C₂₀ alkynyl; (d) up to a C₁₆ carbocycle; (e) up to aC₁₆ heterocycle; and (f) —C(R¹³)_(z)H_((3-z)); or Q′ is a core of astatin molecule; with carbon monoxide (CO) in the presence of acatalytically effective amount of a catalyst of the formula:[Lewis acid]^(u+){[QT(CO)_(v)]^(s−)}^(t)  II wherein: Q is any ligand orset of ligands and need not be present; T is a metal selected from group7, 8, or 9 of the periodic table; s is an integer from 1 to 4 inclusive;t is a number such that t multiplied by s equals u; u is an integer from1 to 6 inclusive; v is an integer from 1 to 9 inclusive; and the Lewisacid is H+ or is of formula [M(L)_(b)]^(c+), wherein M is a transitionmetal or group 13 or 14 metal; L is a ligand and need not be present; bis an integer from 1 to 6, inclusive; and c is 1, 2, or 3; to produce acompound of the formula S-I′:


36. The method of claim 35, wherein the statin molecule is selected fromthe group consisting of: atorvastatin, lovastatin, mevastatin,pravastatin, and simvastatin.
 37. The method of claim 36, wherein thestatin molecule is atorvastatin.
 38. The method of claim 35, wherein the

moiety is selected from the group consisting of:

wherein R^(e) at each occurrence is independently selected from thegroup consisting of: hydrogen; C₁-C₁₂ alkyl; C₂-C₁₂ alkenyl; C₂-C₁₂alkynyl; aryl; heteroaryl; halogen; —OR¹⁰; —OC(O)R¹³; —OC(O)OR¹³;—OC(O)NR¹¹R¹²; —CN; —CNO; —C(O)R¹³; —C(R¹³)_(z)H_((3-z)); —C(O)OR¹³;—C(O)NR¹¹R¹²; —NR¹¹R¹²; —NR¹¹C(O)R¹⁰; —NR¹¹C(O)OR¹³; —NR¹¹SO₂R¹³; —NCO;—N₃; —NO₂; —S(O)_(x)R¹³; —SO₂NR¹¹R¹²; —C(R¹³)_(z)H_((3-z));—(CH₂)_(k)R¹⁴; —(CH₂)_(k)—Z—R¹⁶—; and —(CH₂)_(k)—Z—(CH₂)_(m)—R¹⁴, wheretwo or more R^(e) groups may optionally be taken together to form anoptionally substituted ring; and R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁶, Z, k, m,x, and z are as defined in claim
 1. 39. The method of claim 35, whereinthe

moiety is selected from the group consisting of:

wherein R^(e) at each occurrence is independently selected from thegroup consisting of: hydrogen; C₁-C₁₂ alkyl; C₂-C₁₂ alkenyl; C₂-C₁₂alkynyl; aryl; heteroaryl; halogen; —OR¹⁰; —OC(O)R¹³; —OC(O)OR¹³;—OC(O)NR¹¹R¹²; —CN; —CNO; —C(O)R¹³; —C(R¹³)_(z)H_((3-z)); —C(O)OR¹³;—C(O)NR¹¹R¹²; —NR¹¹R¹²; —NR¹¹C(O)R¹⁰; —NR¹¹C(O)OR¹³; —NR¹¹SO₂R¹³; —NCO;—N₃; —NO₂; —S(O)_(x)R¹³; —SO₂NR¹¹R¹²; —C(R¹³)_(z)H_((3-z));—(CH₂)_(k)R¹⁴; —(CH₂)_(k)—Z—R¹⁶—; and —(CH₂)_(k)—Z—(CH₂)_(m)—R¹⁴, wheretwo or more R^(e) groups may optionally be taken together to form anoptionally substituted ring; and R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁶, Z, k, m,x, and z are as defined in claim
 1. 40. The method of claim 35, whereinthe

moiety is selected from the group consisting of:

wherein R^(e) at each occurrence is independently selected from thegroup consisting of: hydrogen; C₁-C₁₂ alkyl; C₂-C₁₂ alkenyl; C₂-C₁₂alkynyl; aryl; heteroaryl; halogen; —OR¹⁰; —OC(O)R¹³; —OC(O)OR¹³;—OC(O)NR¹¹R¹²; —CN; —CNO; —C(O)R¹³; —C(R¹³)_(z)H_((3-z)); —C(O)OR¹³;—C(O)NR¹¹R¹²; —NR¹¹R¹²; —NR¹¹C(O)R¹⁰; —NR¹¹C(O)OR¹³; —NR¹¹SO₂R¹³; —NCO;—N₃; —NO₂; —S(O)_(x)R¹³; —SO₂NR¹¹R¹²; —C(R¹³)_(z)H_((3-z));—(CH₂)_(k)R¹⁴; —(CH₂)_(k)—Z—R¹⁶—; and —(CH₂)_(k)—Z—(CH₂)_(m)—R¹⁴, wheretwo or more R^(e) groups may optionally be taken together to form anoptionally substituted ring; and R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁶, Z, k, m,x, and z are as defined in claim
 1. 41. The method of claim 36, whereinthe statin molecule is lovastatin.
 42. The method of claim 35, whereinthe

moiety is selected from the group consisting of:

wherein R^(e) at each occurrence is independently selected from thegroup consisting of: hydrogen; C₁-C₁₂ alkyl; C₂-C₁₂ alkenyl; C₂-C₁₂alkynyl; aryl; heteroaryl; halogen; —OR¹⁰; —OC(O)R¹³; —OC(O)OR¹³;—OC(O)NR¹¹R¹²; —CN; —CNO; —C(O)R¹³; —C(R¹³)_(z)H_((3-z)); —C(O)OR¹³;—C(O)NR¹¹R¹²; —NR¹¹R¹²; —NR¹¹C(O)R¹⁰; —NR¹¹C(O)OR¹³; —NR¹¹SO₂R¹³; —NCO;—N₃; —NO₂; —S(O)_(x)R¹³; —SO₂NR¹¹R¹²; —C(R¹³)_(z)H_((3-z));—(CH₂)_(k)R¹⁴; —(CH₂)_(k)—Z—R¹⁶—; and —(CH₂)_(k)—Z—(CH₂)_(m)—R¹⁴, wheretwo or more R^(e) groups may optionally be taken together to form anoptionally substituted ring; and R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁶, Z, k, m,x, and z are as defined in claim
 1. 43. The method of claim 36, whereinthe statin molecule is mevastatin.
 44. The method of claim 35, whereinthe

moiety is selected from the group consisting of:


45. The method of claim 35, wherein the

moiety is selected from the group consisting of:

wherein R^(e) at each occurrence is independently selected from thegroup consisting of: hydrogen; C₁-C₁₂ alkyl; C₂-C₁₂ alkenyl; C₂-C₁₂alkynyl; aryl; heteroaryl; halogen; —OR¹⁰; —OC(O)R¹³; —OC(O)OR¹³;—OC(O)NR¹¹R¹²; —CN; —CNO; —C(O)R¹³; —C(R¹³)_(z)H_((3-z)); —C(O)OR¹³;—C(O)NR¹¹R¹²; —NR¹¹R¹²; —NR¹¹C(O)R¹⁰; —NR¹¹C(O)OR¹³; —NR¹¹SO₂R¹³; —NCO;—N₃; —NO₂; —S(O)_(x)R¹³; —SO₂NR¹¹R¹²; —C(R¹³)_(z)H_((3-z));—(CH₂)_(k)R¹⁴; —(CH₂)_(k)—Z—R¹⁶—; and —(CH₂)_(k)—Z—(CH₂)_(m)—R¹⁴, wheretwo or more R^(e) groups may optionally be taken together to form anoptionally substituted ring; and R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁶, Z, k, m,x, and z are as defined in claim
 1. 46. The method of claim 36, whereinthe statin molecule is pravastatin.
 47. The method of claim 35, whereinthe

moiety is selected from the group consisting of:

wherein R^(e) at each occurrence is independently selected from thegroup consisting of: hydrogen; C₁-C₁₂ alkyl; C₂-C₁₂ alkenyl; C₂-C₁₂alkynyl; aryl; heteroaryl; halogen; —OR¹⁰; —OC(O)R¹³; —OC(O)OR¹³;—OC(O)NR¹¹R¹²; —CN; —CNO; —C(O)R¹³; —C(R¹³)_(z)H_((3-z)); —C(O)OR¹³;—C(O)NR¹¹R¹²; —NR¹¹R¹²; —NR¹¹C(O)R¹⁰; —NR¹¹C(O)OR¹³; —NR¹¹SO₂R¹³; —NCO;—N₃; —NO₂; —S(O)_(x)R¹³; —SO₂NR¹¹R¹²; —C(R¹³)_(z)H_((3-z));—(CH₂)_(k)R¹⁴; —(CH₂)_(k)—Z—R¹⁶—; and —(CH₂)_(k)—Z—(CH₂)_(m)—R¹⁴, wheretwo or more R^(e) groups may optionally be taken together to form anoptionally substituted ring; and R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁶, Z, k, m,x, and z are as defined in claim
 1. 48. The method of claim 35, whereinthe

moiety is selected from the group consisting of:

wherein R^(e) at each occurrence is independently selected from thegroup consisting of: hydrogen; C₁-C₁₂ alkyl; C₂-C₁₂ alkenyl; C₂-C₁₂alkynyl; aryl; heteroaryl; halogen; —OR¹⁰; —OC(O)R¹³; —OC(O)OR¹³;—OC(O)NR¹¹R¹²; —CN; —CNO; —C(O)R¹³; —C(R¹³)_(z)H_((3-z)); —C(O)OR¹³;—C(O)NR¹¹R¹²; —NR¹¹R¹²; —NR¹¹C(O)R¹⁰; —NR¹¹C(O)OR¹³; —NR¹¹SO₂R¹³; —NCO;—N₃; —NO₂; —S(O)_(x)R¹³; —SO₂NR¹¹R¹²; —C(R¹³)_(z)H_((3-z));—(CH₂)_(k)R¹⁴; —(CH₂)_(k)—Z—R¹⁶—; and —(CH₂)_(k)—Z—(CH₂)_(m)—R¹⁴, wheretwo or more R^(e) groups may optionally be taken together to form anoptionally substituted ring; and R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁶, Z, k, m,x, and z are as defined in claim
 1. 49. The method of claim 36, whereinthe statin molecule is simvastatin.
 50. The method of claim 35, whereinthe

moiety is selected from the group consisting of:

wherein R^(e) at each occurrence is independently selected from thegroup consisting of: hydrogen; C₁-C₁₂ alkyl; C₂-C₁₂ alkenyl; C₂-C₁₂alkynyl; aryl; heteroaryl; halogen; —OR¹⁰; —OC(O)R¹³; —OC(O)OR¹³;—OC(O)NR¹¹R¹²; —CN; —CNO; —C(O)R¹³; —C(R¹³)_(z)H_((3-z)); —C(O) OR¹³;—C(O)NR¹¹R¹²; —NR¹¹R¹²; —NR¹¹C(O)R¹⁰; —NR¹¹C(O)OR¹³; —NR¹¹SO₂R¹³; —NCO;—N₃; —NO₂; —S(O)_(x)R¹³; —SO₂NR¹¹R¹²; —C(R¹³)_(z)H_((3-z));—(CH₂)_(k)R¹⁴; —(CH₂)_(k)—Z—R¹⁶—; and —(CH₂)_(k)—Z—(CH₂)_(m)—R¹⁴, wheretwo or more R^(e) groups may optionally be taken together to form anoptionally substituted ring; and R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁶, Z, k, m,x, and z are as defined in claim
 1. 51. The method of claim 6, wherein Xis a phosphorous-containing moiety selected from the group consisting ofa phosphonium salt, a triarylphosphonium, and a phosphonate group. 52.The method of claim 51, wherein the phosphorous containing moiety is aphosphonium salt.
 53. The method of claim 52, wherein the phosphoniumsalt has the formula —[P(R¹³)₃]⁺.
 54. The method of claim 53, whereinthe phosphonium salt is a triarylphosphonium salt.
 55. The method ofclaim 54, wherein the triarylphosphonium salt is triphenylphosphonium.56. The method of claim 51, wherein the phosphorous containing moiety isa phosphonate.
 57. The method of claim 56, wherein the phosphonate hasthe formula —P═O(OR¹⁰)₂.
 58. The method of claim 56, wherein thephosphonate is a dialkyl phosphonate.
 59. The method of claim 58,wherein the dialkyl phosphonate is selected from the group consisting ofdimethyl phosphonate, diethyl phosphonate, di-n-propyl phosphonate,di-1-propyl phosphonate, and dibutyl phosphonate.